Project Summary/Abstract: Approximately one third of the world's population is infected with latent tuberculosis (LTBI). While BCG vaccination protects some children against pediatric tuberculous meningitis, it does not prevent the most prevalent form of disease, pulmonary TB disease in adults. To date, every new tuberculosis (TB) vaccine candidate has failed in large-scale clinical trials and no known immune correlates of vaccine protection for TB have been validated. Failure of new TB vaccines such as MVA-85A, despite generating high-magnitude Th1 immune responses against the immunodominant antigen, Ag85A, is likely related to the exclusive use of immunodominant antigens in these vaccines, despite poor correlation of immunodominant responses with vaccine efficacy. These facts highlight a critical need for discovery of novel subdominant TB antigens for use in TB vaccines that can enhance functional immunity and bacterial killing. Here we propose a novel TB antigen discovery platform that enables systematic and unbiased probing of a TB genome-wide DNA vaccine library with the overall objective to identify new TB antigens. Our specific aims are to generate immune responses to pooled subdominant antigens in mice and to identify novel subdominant immunogens with capacity to induce protective immunity. We aim to do this by in vivo interrogation of the TB proteome using the mouse challenge model. Our long-term goal is to inform TB vaccine design and to uncover novel immune correlates of vaccine protection for TB. Achieving these aims has the capacity to transform the TB vaccine field and contribute to the development of an efficacious TB vaccine. The Barouch laboratory at Beth Israel Deaconess Medical Center leads in vaccine design and discovery for diseases such as HIV and Zika virus infection. I aim to synergize my expertise in TB bacteriology and animal models with enhanced training in immunology and vaccinology at the Center for Virology and Vaccine Research to gain the skills necessary to position myself to become a leader in TB vaccine discovery as a principle investigator and head of my own research group.